The new therapies that became available for advanced melanoma over the past year—the anti-CTLA4 antibody ipilimumab (Yervoy) and the selective BRAF inhibitor vemurafenib (Zelboraf)—represent promising new options for these patients, whose prognosis was heretofore almost universally dismal. However, the advent of new treatment strategies has made treatment decisions more complex.
A panel of three prominent melanoma researchers—Michael Atkins of the Georgetown Lombardi Comprehensive Cancer Center, Keith Flaherty of Massachusetts General Hospital, and Jeffrey Sosman of Vanderbilt Medical Center—drew on recent research to address some of the thornier questions regarding drug selection and drug sequencing in this population.
The advantages of a BRAF inhibitor are its ability to produce a rapid response and its greater potential for staving off early disease progression. Not only do 90% of treatment-nave patients respond, but 90% of patients with prior therapy have an early treatment effect as well. Even in patients with a high disease burden, early vemurafenib data showed a dramatic positron-emission tomography (PET) response. However, the long-term data for vemurafenib are less striking. Long-term response may be compromised in patients who receive vemurafenib relatively late in their disease course, and the responses in some of these patients can be quite short-lived. (They can be quite long-lived in others; however, clinical grounds alone do not provide much insight into which patients will be in the latter group.) Also, while patients with moderate or low disease burden can profitably be transitioned later to another therapy—such as ipilimumab—this is probably not the case for patients with a high disease burden.
Ipilimumab has the advantage of providing more durable responses. However, this immune therapy frequently first produces disease progression, with the response following later. This creates a real dilemma for treating physicians. As Dr. Flaherty put it, “Metastatic melanoma is a race against time.” Some patients will live a year, but others will be dead in 2 to 3 months. And although lactate dehydrogenase (LDH) levels can help risk-stratify patients to some degree, there is still no reliable way to determine who has a year left and who has far less time. Thus, knowing how long to wait to see a response with ipilimumab can be difficult; frequently, hard decisions must be made. Moreover, it is still not possible to determine which patients will demonstrate the hoped-for long-term response to ipilimumab.
In the approximately 50% of patients who have a BRAF V600E mutation, treating physicians weighing these pros and cons have frequently opted for a BRAF inhibitor as the choice for first-line therapy. In patients with symptomatic, bulky, rapidly growing, and high–serum LDH disease, the panel confirmed that this is clearly a sensible choice. Vemurafenib can provide rapid symptom relief and palliation, and these patients are unlikely to be able to benefit from immunotherapy.
However, for the majority of patients with a V600E mutation, the answer is less clear-cut. Dr. Atkins pointed out that recent data suggest that many of these patients may do better if they are started on immunotherapy. He noted that those patients who receive ipilimumab following vemurafenib tend to show the same response to ipilimumab as they exhibited to vemurafenib. However, patients who receive ipilimumab as first-line therapy may get the benefit of a durable response, yet those who exhibit disease progression may still be able to subsequently receive the benefit of treatment with vemurafenib. Interestingly, James Harding and colleagues at Memorial Sloan-Kettering, in a provocative poster presentation, presented evidence of a markedly increased rate of grade 3 hypersensitivity skin reactions in melanoma patients treated with vemurafenib 1 month after ipilimumab therapy. Thus, the definitive answer to the question of which drug to use first in these patients will only come through additional trials. A randomized phase III trial of ipilimumab (followed by vemurafenib) vs vemurafenib (followed by ipilimumab) is currently being planned.
Dr. Sosman noted that treatment options for patients with BRAF wild-type (WT) melanoma are more limited. For those few patients with C-Kit mutations, Kit inhibitors can produce dramatic responses. For the approximately one-third of BRAF WT melanoma patients who have NRAS mutations, interleukin-2 has been shown to produce responses, and thus other immunotherapies (ipilimumab or the newer anti–Programmed Death 1 [anti-PD1] antibodies) might also be tried. In fact, ongoing trials with anti-PD1 antibodies have shown exciting early results in BRAF WT patieints, with response rates of over 20%. MEK inhibitors—either alone or in combination with PI3K inhibitors, AKT inhibitors, or mTOR inhibitors—may also be helpful, although these approaches are still in investigational phases. Dr. Sosman stressed the importance of using tumor mutation profiling to identify novel drivers in the large percentage of patients with BRAF WT melanoma with undefined driver mutations.